Eluxadoline, sold under the brand names Viberzi and Truberzi, is a medication taken by mouth for the treatment of

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

and

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...

in individuals with diarrhea-predominant

irritable bowel syndrome Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...

(IBS-D). It was approved for use in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...

in 2015. The drug originated from

Janssen Pharmaceutica Janssen Pharmaceuticals is a pharmaceutical company headquartered in Beerse, Belgium, and wholly-owned by Johnson & Johnson. It was founded in 1953 by Paul Janssen. In 1961, Janssen Pharmaceuticals was purchased by New Jersey-based American ...

and was developed by

Actavis Actavis Generics (formerly known as Watson Pharmaceuticals and Actavis plc, prior to the acquisition of Irish-based Allergan Inc) is a global pharmaceutical company focused on acquiring, developing, manufacturing and marketing branded pharmaceuti ...

Contraindications

This drug is contraindicated in case of having: * Blockage of the

gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...

or a

sphincter of Oddi The sphincter of Oddi (also hepatopancreatic sphincter or Glisson's sphincter), abbreviated as SO, is a muscular valve that in some animals, including humans, controls the flow of digestive juices (bile and pancreatic juice) out of the pancreas ...

problem * Problems with excessive alcohol use *

Pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...

* Liver problems * Chronic or severe constipation

Adverse effects

Common adverse effects are constipation and nausea, but rates of discontinuation due to constipation were low for both eluxadoline and placebo. Rare adverse effects: fatigue, bronchitis, viral gastroenteritis. Rare serious adverse effects include pancreatitis with a general incidence of 0.3% - higher incidence with 100 mg dose (0.3%) than with 75 mg dose (0.2%). The risk is even greater in those who do not have a

gall bladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...

and the medication is not recommended in this group. In March 2017, the

U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

issued a safety alert for eluxadoline concerning an increased risk of serious pancreatitis in patients without a gallbladder. An FDA review found that in such patients, spasm of the

may lead to severe pancreatitis. The FDA reported that in some cases symptoms have occurred with just one or two doses at the recommended dosage for patients without a gallbladder (75 mg). Of two deaths associated with eluxadoline reported up to February 2017, both occurred in patients without a gallbladder.

Interactions

Elevated concentrations of eluxadoline were observed with co-administration of inhibitors of the transporter protein

OATP1B1 Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the ''SLCO1B1'' gene. Pharmacogenomic research indicates that genetic variations in this gene are associated with response to simvastatin. Clinica ...

, such as: *

Cyclosporine Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease ...

* Gemfibrozil * Certain antiretrovirals *

Rifampin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. It is almost always used tog ...

Eltrombopag Eltrombopag, sold under the brand name Promacta among others, is a medication used to treat thrombocytopenia (abnormally low platelet counts) and severe aplastic anemia. Eltrombopag is sold under the brand name Revolade outside the US and is mar ...

Also, concurrent use of other drugs that cause constipation is not preferred, such as: * Opioids *

Alosetron Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in females only. It was patented in 1987 and approved for medical use in 2 ...

Anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous sys ...

s *

Bismuth subsalicylate Bismuth subsalicylate, sold generically as pink bismuth and under the brand names Pepto-Bismol and BisBacter, is an antacid medication used to treat temporary discomforts of the stomach and gastrointestinal tract, such as nausea, heartburn, indig ...

, potentially dangerous synergism. Eluxadoline increases the concentrations of drugs which are OATP1B1 and BCRP substrates. Also, co-administration of eluxadoline with

rosuvastatin Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat abnormal lipids. It is recommended to be used together with dietary changes, exercise, ...

may increase the risk of rhabdomyolysis.

Pharmacology

Mechanism of action

Eluxadoline is a μ- and

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind op ...

agonist and

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous lig ...

antagonist that acts locally in the

enteric nervous system The enteric nervous system (ENS) or intrinsic nervous system is one of the main divisions of the autonomic nervous system (ANS) and consists of a mesh-like system of neurons that governs the function of the gastrointestinal tract. It is capable of ...

, possibly decreasing adverse effects on the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

Pharmacokinetics

In the ''in vitro'' studies, eluxadoline was found to be transported by OAT3 (

SLC22A8 Solute carrier family 22 member 8, or organic anion transporter 3 (OAT3), is a protein that in humans is encoded by the ''SLC22A8'' gene. Function OAT3 is involved in the transport and excretion of organic ions some of which are drugs (e.g., ...

), OATP1B1 (

SLCO1B1 Solute carrier organic anion transporter family member 1B1 is a protein that in humans is encoded by the ''SLCO1B1'' gene. Pharmacogenomic research indicates that genetic variations in this gene are associated with response to simvastatin. Clinica ...

) and BSEP ( ABCB11) at the highest concentrations tested (400 ng/ml which is 162-fold larger than the observed Cmax of the highest therapeutic dose of 100 mg). However, it was ''not'' to be transported by OCT1

POU2F1 POU domain, class 2, transcription factor 1 is a protein that in humans is encoded by the ''POU2F1'' gene. Interactions POU2F1 has been shown to interact with: * EPRS, * Glucocorticoid receptor, * Glyceraldehyde 3-phosphate dehydrogenase, ...

, OAT1 Organic anion transporter 1, OCT2, OATP1B3 (

SLCO1B3 Solute carrier organic anion transporter family member 1B3 (SLCO1B3) also known as organic anion-transporting polypeptide 1B3 (OATP1B3) is a protein that in humans is encoded by the ''SLCO1B3'' gene. OATP1B3 is a 12-transmembrane domain influx tra ...

), P-gp ( P-glycoprotein), or BCRP ( ABCG2).

Multidrug resistance-associated protein 2 Multidrug resistance-associated protein 2 (MRP2) also called canalicular multispecific organic anion transporter 1 (cMOAT) or ATP-binding cassette sub-family C member 2 (ABCC2) is a protein that in humans is encoded by the ''ABCC2'' gene. Functi ...

(MRP2)-vesicular accumulation of eluxadoline was observed, indicating that the drug is a substrate of MRP2. Eluxadoline was not found to inhibit BCRP-, BSEP-, MRP2-, OCT1-, OCT2-, OAT1-, OAT3-, or OATP1B3-mediated transport of probe substrates but inhibited the transport of probe substrates of OATP1B1 and P-gp. Also in the ''in vitro'' studies, it was observed that eluxadoline is an ''in vivo'' substrate of OATP1B1, OAT3, and MRP2. Finally, no inhibition or induction of

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

enzymes was observed. Following a 100 mg dose of eluxadoline, the C_max was about 2 to 4 ng/ml and AUC was 12-22 ng.h/ml. Eluxadoline has linear pharmacokinetics with no accumulation upon repeated twice daily dosing. Taking eluxadoline with high fat meal decreased the C_max by 50% and AUC by 60%.

Chemistry

Synthesis

The synthesis of eluxadoline was extensively discussed in the patent No. WO2006099060 A2, with the title : "Process for the preparation of opioid modulators" which was published in Sept. 2006
Process of the Preparation of Opioid modulators.

References

{{Irritable bowel syndrome Amines Antidiarrhoeals Carbamates Delta-opioid receptor antagonists Diarrhea Imidazoles AbbVie brands Janssen Pharmaceutica Kappa-opioid receptor agonists Mu-opioid receptor agonists Peripherally selective drugs